Noninvasive determination of upper airway resistance and flow limitation.

We have shown that a polynomial equation, FP = AP3 + BP2 + CP + D, where F is flow and P is pressure, can accurately determine the presence of inspiratory flow limitation (IFL). This equation requires the invasive measurement of supraglottic pressure. We hypothesized that a modification of the equation that substitutes time for pressure would be accurate for the detection of IFL and allow for the noninvasive measurement of upper airway resistance. The modified equation is Ft = At3 + Bt2 + Ct + D, where F is flow and t is time from the onset of inspiration. To test our hypotheses, data analysis was performed as follows on 440 randomly chosen breaths from 18 subjects. First, we performed linear regression and determined that there is a linear relationship between pressure and time in the upper airway (R2 0.96 +/- 0.05, slope 0.96 +/- 0.06), indicating that time can be a surrogate for pressure. Second, we performed curve fitting and found that polynomial equation accurately predicts the relationship between flow and time in the upper airway (R2 0.93 +/- 0.12, error fit 0.02 +/- 0.08). Third, we performed a sensitivity-specificity analysis comparing the mathematical determination of IFL to manual determination using a pressure-flow loop. Mathematical determination had both high sensitivity (96%) and specificity (99%). Fourth, we calculated the upper airway resistance using the polynomial equation and compared the measurement to the manually determined upper airway resistance (also from a pressure-flow loop) using Bland-Altman analysis. Mean difference between calculated and measured upper airway resistance was 0.0 cmH2O x l(-1) x s(-1) (95% confidence interval -0.2, 0.2) with upper and lower limits of agreement of 2.8 cmH2O x l(-1) x s(-1) and -2.8 cmH2O x l(-1) x s(-1). We conclude that a polynomial equation can be used to model the flow-time relationship, allowing for the objective and accurate determination of upper airway resistance and the presence of IFL.     

Preliminary palynological investigation of Saudi Arabian Upper Ordovician glacial sediments

An Ordovician stratigraphically admixed palynomorph assemblage that contains palynomorphs eroded from Middle through Upper Ordovician strata characterizes the Hawban Member (restricted) of the Sarah Formation in central Saudi Arabia. This distinctive assemblage, combined with detailed sedimentology, helps identify the presence of Hirnantian Gondwanan glacial sediments on the Arabian Plate. Similar Ordovician admixed assemblages have been recognized from Upper Ordovician glacial sediments elsewhere along the Gondwanan margin. Within Saudi Arabia the composition of reworked assemblages depends upon the stratigraphic succession exposed to glacial erosion. Sylvanidium? hawbanense, which is one of the acritarchs found in glacial sediments, is newly described from Arabian Upper Ordovician strata.     

Pixantrone can be activated by formaldehyde to generate a potent DNA adduct forming agent

Mitoxantrone is an anti-cancer agent used in the treatment of breast and prostate cancers. It is classified as a topoisomerase II poison, however can also be activated by formaldehyde to generate drug-DNA adducts. Despite identification of this novel form of mitoxantrone-DNA interaction, excessively high, biologically irrelevant drug concentrations are necessary to generate adducts. A search for mitoxantrone analogues that could potentially undergo this reaction with DNA more efficiently identified Pixantrone as an ideal candidate. An in vitro crosslinking assay demonstrated that Pixantrone is efficiently activated by formaldehyde to generate covalent drug-DNA adducts capable of stabilizing double-stranded DNA in denaturing conditions. Pixantrone-DNA adduct formation is both concentration and time dependent and the reaction exhibits an absolute requirement for formaldehyde. In a direct comparison with mitoxantrone-DNA adduct formation, Pixantrone exhibited a 10- to 100-fold greater propensity to generate adducts at equimolar formaldehyde and drug concentrations. Pixantrone-DNA adducts are thermally and temporally labile, yet they exhibit a greater thermal midpoint temperature and an extended half-life at 37 degrees C when compared to mitoxantrone-DNA adducts. Unlike mitoxantrone, this enhanced stability, coupled with a greater propensity to form covalent drug-DNA adducts, may endow formaldehyde-activated Pixantrone with the attributes required for Pixantrone-DNA adducts to be biologically active.     

Geographic patterns in the distribution of Palearctic songbirds

A database was created of digitized equal area distribution maps of 3,036 phylogenetic species of Palearctic songbirds. Biogeographic patterns are reported for two data sets: (1) including all passeriform bird species reported as breeding within the boundaries of our study map, (2) passeriform species restricted in their distribution to our study region, thus excluding the partly extra-limital taxa. With respect to the data set excluding partly extra-limital taxa, the average range size is 238 grid cells (grid cell area: 4,062 km²). Analysis of the geographic distribution of species richness for the full data set showed several hotspot regions, mostly located in mountainous areas. The index of range-size rarity identified similar hotspot regions as that for species richness, albeit that the range-size rarity de-emphasized the central Siberian hotspot. Range-size rarity hotspots that are not evident on the measure of species richness concern a great number of islands. Much more prominent on the index of range-size rarity are the Atlas Mountains of northern Africa, the Jabal al Akhdar region in NE Libya, and the eastern border of the Mediterranean. Restricting the analysis of geographic variation to the 25% of the species with smallest ranges resulted in a greatly simplified pattern of hotspots. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

How Ebola and Marburg viruses battle the immune system

The filoviruses Ebola and Marburg have emerged in the past decade from relative obscurity to serve now as archetypes for some of the more intriguing and daunting challenges posed by such agents. Public imagination is captured by deadly outbreaks of these viruses and reinforced by the specter of bioterrorism. As research on these agents has accelerated, it has been found increasingly that filoviruses use a combination of familiar and apparently new ways to baffle and battle the immune system. Filoviruses have provided thereby a new lens through which to examine the immune system itself.     

Raman characterization and chemical imaging of biocolloidal self-assemblies, drug delivery systems, and pulmonary inhalation aerosols: A review

This review presents an introduction to Raman scattering and describes the various Raman spectroscopy, Raman microscopy, and chemical imaging techniques that have demonstrated utility in biocolloidal self-assemblies, pharmaceutical drug delivery systems, and pulmonary research applications. Recent Raman applications to pharmaceutical aerosols in the context of pulmonary inhalation aerosol delivery are discussed. The "molecular fingerprint" insight that Raman applications provide includes molecular structure, drug-carrier/excipient interactions, intramolecular and intermolecular bonding, surface structure, surface and interfacial interactions, and the functional groups involved therein. The molecular, surface, and interfacial properties that Raman characterization can provide are particularly important in respirable pharmaceutical powders, as these particles possess a higher surface-area-to-volume ratio; hence, understanding the nature of these solid surfaces can enable their manipulation and tailoring for functionality at the nanometer level for targeted pulmonary delivery and deposition. Moreover, Raman mapping of aerosols at the micro- and nanometer level of resolution is achievable with new, sophisticated, commercially available Raman microspectroscopy techniques. This noninvasive, highly versatile analytical and imaging technique exhibits vast potential for in vitro and in vivo molecular investigations of pulmonary aerosol delivery, lung deposition, and pulmonary cellular drug uptake and disposition in unfixed living pulmonary cells.     

Base-CP proteasome can serve as a platform for stepwise lid formation

26S proteasome, a major regulatory protease in eukaryotes, consists of a 20S proteolytic core particle (CP) capped by a 19S regulatory particle (RP). The 19S RP is divisible into base and lid sub-complexes. Even within the lid, subunits have been demarcated into two modules: module 1 (Rpn5, Rpn6, Rpn8, Rpn9 and Rpn11), which interacts with both CP and base sub-complexes and module 2 (Rpn3, Rpn7, Rpn12 and Rpn15) that is attached mainly to module 1. We now show that suppression of RPN11 expression halted lid assembly yet enabled the base and 20S CP to pre-assemble and form a base-CP. A key role for Regulatory particle non-ATPase 11 (Rpn11) in bridging lid module 1 and module 2 subunits together is inferred from observing defective proteasomes in rpn11–m1, a mutant expressing a truncated form of Rpn11 and displaying mitochondrial phenotypes. An incomplete lid made up of five module 1 subunits attached to base-CP was identified in proteasomes isolated from this mutant. Re-introducing the C-terminal portion of Rpn11 enabled recruitment of missing module 2 subunits. In vitro, module 1 was reconstituted stepwise, initiated by Rpn11–Rpn8 heterodimerization. Upon recruitment of Rpn6, the module 1 intermediate was competent to lock into base-CP and reconstitute an incomplete 26S proteasome. Thus, base-CP can serve as a platform for gradual incorporation of lid, along a proteasome assembly pathway. Identification of proteasome intermediates and reconstitution of minimal functional units should clarify aspects of the inner workings of this machine and how multiple catalytic processes are synchronized within the 26S proteasome holoenzymes.